1 Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2 Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
3 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA; Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA.
4 Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
5 Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania, USA.
6 Division of Nephrology, Department of Medicine, Western University, London, Ontario, Canada.
7 Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California, USA; Division of Research, Kaiser Permanente Northern California, Oakland, California, USA; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.
8 Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.
9 Division of Nephrology, New York University School of Medicine, New York, New York, USA; Divison of Nephrology, VA New York Harbor Healthcare System, New York, New York, USA.
10 National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA; National Institutes of Health, Bethesda, Maryland, USA.
11 Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA.
12 Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
13 Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address: chirag.parikh@jhmi.edu.
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Steven Menez et al.
Kidney Int..
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Affiliations
1 Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2 Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
3 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA; Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA.
4 Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
5 Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania, USA.
6 Division of Nephrology, Department of Medicine, Western University, London, Ontario, Canada.
7 Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California, USA; Division of Research, Kaiser Permanente Northern California, Oakland, California, USA; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.
8 Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.
9 Division of Nephrology, New York University School of Medicine, New York, New York, USA; Divison of Nephrology, VA New York Harbor Healthcare System, New York, New York, USA.
10 National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA; National Institutes of Health, Bethesda, Maryland, USA.
11 Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA.
12 Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
13 Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address: chirag.parikh@jhmi.edu.
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Abstract
Biomarkers of tubular function such as epidermal growth factor (EGF) may improve prognostication of participants at highest risk for chronic kidney disease (CKD) after hospitalization. To examine this, we measured urinary EGF (uEGF) from samples collected in the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study, a multi-center, prospective, observational cohort of hospitalized participants with and without AKI. Cox proportional hazards regression was used to investigate the association of uEGF/Cr at hospitalization, three months post-discharge, and the change between these time points with major adverse kidney events (MAKE): CKD incidence, progression, or development of kidney failure. Clinical findings were paired with mechanistic studies comparing relative Egf expression in mouse models of kidney atrophy or repair after ischemia-reperfusion injury. MAKE was observed in 20% of 1,509 participants over 4.3 years of follow-up. Each 2-fold higher level of uEGF/Cr at three months was associated with decreased risk of MAKE (adjusted hazards ratio 0.46, 95% confidence interval: 0.39-0.55). Participants with the highest increase in uEGF/Cr from hospitalization to three-month follow-up had a lower risk of MAKE (adjusted hazards ratio 0.52; 95% confidence interval: 0.36-0.74) compared to those with the least change in uEGF/Cr. A model using uEGF/Cr at three months combined with clinical variables yielded moderate discrimination for MAKE (area under the curve 0.73; 95% confidence interval: 0.69-0.77) and strong discrimination for kidney failure at four years (area under the curve 0.96; 95% confidence interval: 0.92-1.00). Accelerated restoration of Egf expression in mice was seen in the model of adaptive repair after injury, compared to a model of progressive atrophy. Thus, urinary EGF/Cr may be a biomarker of distal tubular health, with higher concentrations and increased uEGF/Cr post-discharge independently associated with reduced risk of MAKE in hospitalized patients.
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